Kaposi's sarcoma associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a proportion of Castelman's disease. We have been interested in elucidating the pathogenetic mechanisms underlying KSHV-associated diseases and exploring stratetegies for treatment. Kaposi's sarcoma (KS), the most common neoplasm in AIDS patients, typically presents with multiple skin lesions characterized by "spindle cells", the vast majority of which are infected with KSHV (Kaposi's sarcoma herpes virus, also named HHV-8). In patients with AIDS, the presence of cell-associated KSHV-DNA in blood is predictive of subsequent KS development, but the mechanisms by which circulating KSHV-infected cells contribute to AIDS-KS pathogenesis are unclear. Our previous studies had detected selective expression of the chemokine SDF-1 in the capillary endothelium of skin, lymph nodes and bone marrow sinusoids, but not usually other sites. Other studies had detected SDF-1 production in angiogenic endothelium. We now found that SDF-1, which is constitutively expressed by skin capillary endothelium and displayed on the endothelial cell surface in association with heparan sulfate, can trigger specific arrest of KSHV-infected cells under physiological shear flow conditions. Moreover, we discovered that SDF-1 expressed on the endothelial barrier promotes transendothelial migration of KSHV-infected cells in the presence of tissue chemokine gradients. By triggering specific adhesion of circulating KSHV-infected cells and favoring their entry into the extravascular cutaneous space, endothelial cell-associated SDF-1 in cutaneous capillaries may dictate the preferential occurrence of KS in the skin. A condition for tissue SDF-1 gradients to be effective and promote cell adhesion and migration is that SDF-1 is either absent/present at very low concentrations or inactive in the circulation. We measured SDF-1 levels in blood of normal individuals and patients with AIDS with or without Kaposi's sarcoma and determined SDF-1 levels to be approximately 16 ng/ml in normal and patient blood. In addition, we found SDF-1 to be cleaved and inactive in the circulation due to the removal of two N-terminal residues (KP) due to the action of a dipeptidase, and the removal of the C-terminal K by the enzyme Carboxypeptidase N. Heparan sulpate proteoglycans, abundant on the cell surface can avidly bind SDF-1 and protect it from enzymatic degradation. Thus, SDF-1 is present at nanogram/ml concentration in blood and is found as an active molecule bound to the endothelial cell surface at selected sites. In the skin, SDF-1 likely contributes to the arrest and transmigration of circulating KSHV-infected cells to the extracellular space thereby contributing to disease pathogenesis. Thus, blocking SDF-1/receptor interactions may represent an important therapeutic approach to the prevention of KSHV diseases in infected individuals.